Differential potentiative effects of GABA receptor agonists in the production of antinociception induced by morphine and beta-endorphin administered intrathecally in the mouse

The effect of muscimol or baclofen injected intrathecally (i.t.) on the inhibition of the tail-flick response induced by morphine and beta-endorphin administered i.t. was studied in ICR mice. The i.t. injection of muscimol (100 ng) or baclofen (10 ng) alone did not affect the basal inhibition of the tail-flick response. Morphine (0.2 microg) and beta-endorphin (0.1 microg) caused only slight inhibition of the tail-flick response. Baclofen, but not muscimol, injected i.t. enhanced the inhibition of the tail-flick response induced by i.t. administered morphine. Both muscimol and baclofen injected i.t. significantly enhanced i.t. injected beta-endorphin-induced inhibition of the tail-flick response. Our results suggest that the GABA(B), but not GABA(A), receptors located in the spinal cord appear to be involved in enhancing the inhibition of the tail-flick response induced by morphine administered spinally. In addition, both GABA(A) and GABA(B) receptors are involved in enhancing the inhibition of the tail-flick response induced by beta-endorphin administered i.t.     

The influence of indomethacin on the acth secretion induced by central stimulation of adrenergic receptors.

We had previously demonstrated that indomethacin affected the corticosterone secretion induced by central stimulation of alpha-but not beta-adrenergic receptors in conscious rats. In the present study we investigated whether hypothalamic and/or pituitary prostaglandins (PGs) were involved in the central adrenergic stimulation of ACTH secretion. Indomethacin, 2 mg/kg ip or 10 microg intracerebroventricularly (icv), was administered 15 min before phenylephrine (30 microg icv), an alpha-adrenergic agonist, clonidine (10 microg), an alpha2-adrenergic agonist, and isoprenaline (20 microg) or clenbuterol (10 microg), a beta1- or beta2-adrenergic agonist. One hour after the last injection the rats were decapitated and plasma levels of ACTH were measured. The present results show that the ACTH responses induced by icv administration of phenylephrine and clonidine were considerably impaired by icv or ip pretreatment with indomethacin, an inhibitor of prostaglandin synthesis. Indomethacin given by either route only slightly diminished the isoprenaline-induced ACTH response and did not substantially alter the clenbuterol-induced response. The adrenergic-induced ACTH responses were more potently inhibited by ip than by icv pretreatment with indomethacin, which may result from a stronger inhibition of PGs synthesis in the median eminence and anterior pituitary by ip pretreatment with indomethacin than in hypothalamic structures by its icv administration. These results indicate a significant involvement of PGs in central stimulation of the hypothalamic-pituitary adrenal (HPA) axis by alpha1- and alpha2- but not beta-adrenergic receptors.     

Effect of GABA agonists on the neurotoxicity and anticonvulsant activity of benzodiazepines

Progabide (50 mg/kg, i.p.), a GABA receptor agonist, significantly decreases the median minimal neurotoxic dose (TD50) of clobazam, chlordiazepoxide, and diazepam; the receptor binding of these substances is highly enhanced by muscimol. Progabide has no significant effect on the TD50 of clonazepam and triazolam; the receptor bindings of these substances is either only slightly enhanced or not altered by muscimol. Progabide also significantly decreases the median antimaximal electroshock dose (MES ED50) of all the benzodiazepines tested. However, progabide has no effect on the median antipentylenetetrazol dose (PTZ ED50) of the benzodiazepines. Likewise, THIP (2.5 mg/kg, i.p.) significantly decreases the TD50 of chlordiazepoxide but not that of triazolam. THIP significantly decreases the MES ED50 of chlordiazepoxide and triazolam but has no effect on the PTZ ED50 of these two substances. The above data suggest that benzodiazepine receptors linked to GABA receptors contribute to the minimal neurotoxicity and anti-MES activity but not to the anti-PTZ activity of benzodiazepines.     

Catecholaminergic regulation of the hypothalamic-pituitary-adrenocortical activity.

The significance and site of adrenergic receptors involved in the control of the hypothalamic-pituitary-adrenal axis (HPA) activity was assessed indirectly by estimation of serum corticosterone levels 1 h after drug administration to conscious rats. Adrenergic drugs were given intracerebroventricularly (icv) and intraperitoneally (ip), the antagonists 15 min prior to the agonists. Noradrenaline, adrenalin and isoproterenol given by either route increased dose-dependently the serum corticosterone levels. The corticosterone response to icv noradrenaline was almost abolished by icv pretreatment with propranolol, a beta-adrenergic antagonist, and yohimbine, and alpha 2-receptor blocker, and was also considerably reduced by prazosin, an alpha 1-adrenergic antagonist. When given ip, these antagonists did not significantly influence the noradrenaline induced corticosterone response, which suggests a suprapituitary site of action of noradrenaline in stimulation of the HPA. The corticosterone response to icv adrenalin was suppressed by prazosin given by either route. The corticosterone response to ip adrenalin was almost abolished by pretreatment with yohimbine, and also significantly diminished by propranolol given by the same route. The increase in corticosterone secretion, induced by isoproterenol given by either route, was abolished by ip injection of propranolol. These results indicate that noradrenaline stimulates the HPA via alpha- and beta-adrenergic receptors, mainly at the suprapituitary level. Adrenalin increases that activity both via central and pituitary alpha- and beta-adrenoceptors. Isoproterenol activates the HPA by stimulation of pituitary beta-receptors.     

Effect of indomethacin on the CRH- and VP-induced pituitaryadrenocortical response during social stress

The role of prostaglandins (PGs) on the corticotropin-releasing hormone (CRH)- and vasopressin (AVP)-induced pituitary-adrenocortical response under basal and social stress circumstances was investigated. Crowding stress applied for 3 days did not diminish the CRH-elicited corticosterone response, but it considerably reduced such a response to AVP. In control rats systemic or icv pretreatment with indomethacin, an inhibitor of PGs synthesis, did not affect the corticosterone response to ip or icv CRH administered 15 min later. By contrast, ip or icv pretreatment with indomethacin considerably reduced the corticosterone response to AVP given by either route in control rats. Similarly, ip pretreatment with indomethacin further reduced the corticosterone response to AVP already diminished by crowding stress. These results indicate that hypothalamic and anterior pituitary PGs are not involved in the CRH-elicited pituitary- adrenocortical response, but they significantly mediate this response to AVP under both basal and social stress circumstances.     

Role of the GABA-ergic systems of the brain in manifesting the activating effect of diazepam]

It was shown in experiments on rats that the selective blocker of GABA receptors bicuculline (2 mg/kg) does not decrease the activating effect of diazepam as to the reaction of self-stimulation. The GABA-mimetic muscimol (0.5 and 1 mg/kg) had no effect on self-stimulation rate, while in the dose of 2 mg/kg causing behavioral changes produced a powerful decrease in it (by 93.3%). During the combined administration of diazepam and muscimol (1 mg/kg and 0.5 mg/kg, respectively) no potentiation of diazepam effect was observed. It is suggested that diazepam-induced facilitation of the reaction of self-stimulation is not due to the alteration in the activity of GABA-ergic processes.     

Effect of L-NAME, a specific nitric oxide synthase inhibitor, on corticotropin-releasing hormone-elicited ACTH and corticosterone secretion.

This study was designed to determine the role of endogenous nitric oxide (NO) in the corticotropin-releasing hormone (CRH)-induced ACTH and corticosterone secretion, as well as possible involvement of hypothalamic dopamine and noradrenaline in that secretion in conscious rats. CRH given i.p. stimulated dose-dependently the pituitary-adrenocortical activity measured 1 h later. Dexamethasone (0.2 mg/kg i.p.) injected 1 h before CRH (1 microg/kg i.p.) totally abolished the CRH-elicited ACTH and corticosterone secretion, indicating a predominantly pituitary site of CRH-evoked stimulation. L-arginine (120 mg/kg i.p.) and N(omega)-nitro-L-arginine methyl ester (L-NAME 5-10 mg/kg i.p.) did not markedly affect the basal plasma ACTH and corticosterone levels. L-NAME given 15 min before CRH markedly, but not significantly, augmented the CRH-induced ACTH response, and enhanced more potently and significantly the corticosterone response. Pretreatment with L-arginine, a substrate for NOS, slightly diminished the CRH-induced ACTH response and considerably reduced the corticosterone response. L-arginine also significantly reversed the L-NAME-evoked increase in the CRH-induced ACTH and corticosterone secretion. L-NAME did not markedly alter the CRH-induced hypothalamic dopamine and noradrenaline levels, while L-arginine significantly increased noradrenaline level. However, those alterations were not directly correlated with the observed changes in ACTH and corticosterone secretion. These results indicate that in conscious rats NO plays a marked inhibitory role in the CRH-induced ACTH secretion and inhibits more potently corticosterone secretion. Hypothalamic dopamine and noradrenaline do not seem to be directly involved in the observed alterations in ACTH and corticosterone secretion.     

Effect of subdiaphragmatic vagotomy and cholinergic agents in the hypothalamic-pituitary-adrenal axis activity.

In the present study, we examined whether the vagus nerve is involved in mediating the stimulation of hypothalamic-pituitary-adrenal (HPA) axis by cholinergic muscarinic and nicotinic agonists, carbachol and nicotine. The site of HPA axis muscarinic stimulation was determined using peripheral (i.p.) and intracerebroventricular (i.c.v.) administration of carbachol, atropine sulphate (AtrS) and atropine hydrobromide (AtrBr). The i.p. carbachol-(0.5 mg/kg)-induced corticosterone response was significantly reduced by i.p. pretreatment with AtrBr (0.1 mg/kg), but was not diminished by i.c.v. AtrS (0.1 mug). The increase in corticosterone secretion induced by i.c.v. carbachol (2 microg) was totally abolished by i.c.v. pretreatment with AtrS (0.1 microg) but was not altered by i.p. AtrBr. Subdiaphragmatic vagotomy performed 2 weeks earlier substantially decreased the i.p. carbachol (0.2 mg/kg)-induced ACTH response and markedly augmented ACTH and corticosterone response to a higher dose of carbachol (0.5 mg/kg) in comparison with the responses in sham operated rats. Vagotomy abolished the stimulatory effect of i.p. nicotine in a low dose (1 mg/kg) on ACTH and corticosterone secretion; the ACTH response to higher dose (2.5 mg/kg) was considerably reduced, while corticosterone response remained unaffected. These results suggest that carbachol given i.c.v. evokes considerable corticosterone response by stimulation of central cholinergic muscarinic receptors. A major part of the i.p. carbachol-induced corticosterone secretion results from peripheral cholinergic muscarinic receptor stimulation. Subdiaphragmatic vagotomy moderately intensified the carbachol-induced ACTH and corticosterone secretion. Vagotomy significantly reduced the nicotine-induced ACTH secretion, possibly by the involvement of vagal afferents. The nicotine-induced corticosterone secretion is not exclusively regulated by circulating ACTH but by various intra-adrenal regulatory components.     

Endotoxin administration increases hypothalamic somatostatin mRNA through nitric oxide release

Acute inflammation induced by endotoxin (LPS) administration inhibits insulin-like growth factor (IGF-I) and growth hormone (GH) secretion. The aim of this study was to elucidate the role of glucocorticoids and nitric oxide (NO) in the effect of LPS on hypothalamic somatostatin gene expression. Adult male Wistar rats were injected with different doses of LPS (5, 10 and 100 microg/kg). Rats received two i.p. injections of LPS (at 17:30 and 8:30 h the following day) and were killed 4 h after the second injection. LPS administration at the dose of 100 microg/kg increased the hypothalamic somatostatin mRNA content, as well as the serum concentrations of corticosterone. Glucocorticoids do not seem to be involved in LPS-induced increase in hypothalamic somatostatin mRNA since adrenalectomy did not prevent this effect. In order to analyze the possible effect of NO, aminoguanidine, an inducible nitric oxide synthase inhibitor, was injected (100 mg/kg s.c.) simultaneously with LPS injection. Aminoguanidine administration did not modify somatostatin mRNA in saline injected rats, but it prevented LPS-induced increase in hypothalamic somatostatin mRNA. These data suggest that the stimulatory effect of endotoxin on hypothalamic somatostatin gene expression is not mediated by glucocorticoids, but instead by the increase in NO release.     

Comparison between pentobarbital- and muscimol-induced feeding in satiated sheep

Twenty sheep were used to study the mechanisms by which the intracerebral administration of pentobarbital and of muscimol induces feeding in ruminants. Injections of 1 mumol calcium induced a weak feeding response at 1 h postinjection compared with control values (108 vs. 63 g, p less than 0.05). Injections of 78 mumol pentobarbital and of 100 nmol muscimol elicited strong feeding responses (p less than 0.01). A preinjection of 1 mumol calcium reduced the response to pentobarbital by about 40% but did not affect the response to muscimol. Administration of 1.1 mmol sodium chloride reduced the effect to pentobarbital by about 60% but only partially decreased the effect to muscimol. Administration of picrotoxin, a GABA antagonist, slightly decreased the feeding response to pentobarbital and to muscimol. Administration of gamma-vinyl GABA, an inhibitor of the enzyme GABA transaminase, did not affect feeding behavior of sheep at any of the doses tested (0-10 mumol). Injections of gamma-vinyl GABA followed by equimolar injections of GABA failed to provoke any feeding response. The data suggest that pentobarbital and muscimol may induce feeding by acting on a similar hypothalamic receptor complex but by different mechanisms. The lack of effect of GABA itself remains unexplained.     

Contribution of infralimbic cortex in the cardiovascular response to acute stress

The infralimbic region of the medial prefrontal cortex (IL) modulates autonomic and neuroendocrine function via projections to subcortical structures involved in the response to stress. We evaluated the contribution of the IL to the cardiovascular response evoked by acute stress. Under anesthesia (80 mg/kg ketamine-11.5 mg/kg xylazine), rats were implanted with telemetry probes or arterial lines for recording heart rate and blood pressure. Guide cannulas were implanted to target the IL for microinjection of muscimol (100 pmol/100 nl), N-methyl-d-aspartate (NMDA) (6 pmol/100 nl), or vehicle (100 nl). Microinjection of muscimol, an agonist of GABA(A) receptors, into the IL had no effect on stress-evoked cardiovascular and thermogenic changes in any of the paradigms evaluated (cage switch, restraint plus air-jet noise, or air-jet stress). However, microinjection of the excitatory amino acid NMDA into the IL attenuated the pressor and tachycardic response to air-jet stress. Pretreatment with the selective NMDA antagonist dl-2-amino-5-phosphonopentanoic acid (AP-5, 100 pmol/100 nl) blocked the effect of NMDA on the cardiovascular response to air-jet stress. We conclude that 1) the IL region is not tonically involved in cardiovascular or thermogenic control during stress or under baseline conditions, and 2) activation of NMDA receptors in the IL can suppress the cardiovascular response to acute stress exposure.     

Antinociceptive action of GABA-mimetic agent--N-phthaloyl GABA

N-phthaloyl GABA (P-GABA), a nonselective GABA-ergic drug, showed positive analgesic response in four different models in mice, viz-tail immersion, tail clip, hot plate and writhing-induced by acetic acid. Antinociceptive ED50 (ip in mice) of P-GABA was lowest in tail immersion method (ED50 = 24.27, mg/kg). Though pethidine (10 mg/kg, ip) significantly potentiated the antinociceptive action of P-GABA (20 mg/kg, ip), pretreatment of naloxone (5 mg/kg, im) did not influence the same. Pretreatment with atropine (10 mg/kg, im), picrotoxin (0.08 mg/kg) and 3-mercaptopropionic acid (2 mg/kg) reduced the antinociceptive action of P-GABA significantly. But pretreatment with bicuculline (0.4 mg/kg), a specific GABA antagonist, did not reduce the antinociceptive action of P-GABA.     

Central histaminergic involvement during stress in rats.

Effects of some drugs modulating central histaminergic (HA) transmission were evaluated on restraint stress (RS)-induced gastric ulcerogenesis, plasma corticosterone and immune responses in rats. RS for (i) 6 hr or (ii) 24 hr at room temperature, and (iii) 3 hr at 4 degrees C (CRS) all induced gastric mucosal erosions and elevated plasma corticosterone levels, the effects with the latter two RS procedures being most consistent. Pretreatment of rats with neuronal HA depletor, alpha-FMH (100 mg/kg, ip) attenuated both ulcer severity and corticosterone response, during both 24 hr RS and CRS. Similar effects were also seen with the mast cell degranulator, C-48/80 (10 micrograms/kg, i.c.v.) treatment. Further, the H1-blocker, pheniramine (25 mg/kg, ip) but not the centrally acting H2-blocker, zolantidine (5 mg/kg, ip) produced clearcut attenuations in both stress markers, during the experimental stressors. In rats immunized in SRBC, 24 hr RS (and not CRS) significantly prevented the humoral immune responses to the antigen. alpha-FMH, C 48/80 and pheniramine but not zolantidine, reversed this response during 24 hr RS. The results indicate a central HA ergic involvement in the visceral, endocrinal and immune responses during RS and suggest the probable role of both neuronal as well as extraneuronal (mast cell) HA and activation of H1-receptors in the mediation of these effects.     

Effect of adrenergic antagonists and cyclooxygenase inhibitors on the nicotine-induced hypothalamic-pituitary-adrenocortical activity.

Nicotine is a potent stimulus for the hypothalamic-pituitary-adrenal (HPA) axis. Systemic nicotine acts via central mechanisms to stimulate by multiple pathways the release of ACTH from the anterior pituitary corticotrops and corticosterone from the adrenal cortex. Nicotine may stimulate indirectly the hypothalamic paraventricular nucleus, the site of the corticotropin-releasing hormone (CRH) neurons which activates ACTH release. In the present studies an involvement of adrenergic system and prostaglandins synthesized by constitutive cyclooxygenase (COX-1) and inducible cyclooxygenase (COX-2) in the nicotine-induced HPA response in rats was investigated. Nicotine (2.5-5 mg/kg i.p.) significantly increased plasma ACTH and corticosterone levels measured 1 hr after administration. Adrenergic receptor antagonists or COX inhibitors were injected i.p. 15 min prior to nicotine and the rats were decapitated 1 hr after the last injection. Prazosin (0.01-0.1 mg/kg), an alpha1-adrenergic antagonist, significantly decreased the nicotine-evoked ACTH and corticosterone secretion. Yohimbine (0.1-1.0 mg/kg), an alpha2-adrenergic antagonist, moderately diminished ACTH response, and propranolol (0.1-10 mg/kg), a beta-adrenergic antagonist, did not significantly alter the nicotine-induced hormones secretion. Pretreatment with piroxicam (0.2-2.0 mg/kg), a COX-1 inhibitor, considerably impaired the nicotine-induced ACTH and corticosterone secretion. Compound NS-398 (0.2-5.0 mg/kg), a selective COX-2 blocker did not markedly alter these hormones secretion, and indomethacin (2 mg/kg), a non-selective COX inhibitor significantly diminished ACTH response. These results indicate that systemic nicotine stimulates the HPA axis indirectly, and both adrenergic system and prostaglandins are significantly involved in this stimulation. Noradrenaline, stimulating postsynaptic alpha1-adrenergic receptors, and prostaglandins, synthesized by COX-1 isoenzyme, are of crucial significance in the nicotine-induced ACTH and corticosterone secretion.     

Sensitivity of embryonic spontaneous motility to the GABA agonists baclofen and muscimol

The development of the sensitivity of spontaneous motor activity to the GABA agonists baclofen (10 mg/kg egg weight, systemic administration) and muscimol (0.8 mg/kg e.w., systemic administration) was tested in 11-day to 19-day-old chick embryos. 1) Baclofen already significantly depressed the frequency of spontaneous movements in 11-day embryos; its effect attained the maximum (85% depression of spontaneous motility) in 13-day embryos. After the 15th day of incubation, it reduced spontaneous motor activity by 50-60%. In spinal embryos, baclofen had the same, but a quantitatively more pronounced effect, demonstrated from its direct action on the spinal cord uninfluenced by supraspinal modulation, which began to be manifested after the 15th day of incubation. 2) Muscimol did not begin to inhibit spontaneous motility significantly until the 13th day of incubation. Subsequently, the latent period of its effect shortened, its duration lengthened and, lastly, its quantitative result also increased. 3) A comparison of the effect of GABA (Sedlácek 1978), muscimol and baclofen in 17-day chick embryos showed that the depressive effect increased in the sequence baclofen less than GABA less than muscimol, but that GABA took effect faster than the others. The results testify that the maturation of the individual elements of the GABA-ergic central inhibition system is a complex process.     

Evidence for GABA involvement in stress-induced inhibition of male amphibian sexual behavior

The behavioral effects of GABA analogs were investigated to determine whether GABAergic neurotransmission is involved in the stress-induced inhibition of masculine sexual behaviors in rough-skinned newts (Taricha granulosa). Injections of bicuculline, a GABA antagonist, stimulated male sexual behaviors in a dose-dependent fashion, and the minimum effective dose was 40-fold less when administered centrally rather than systemically, suggesting a central nervous system site of action. Injections of muscimol, a GABA agonist, suppressed reproductive behaviors in male newts, and this inhibition lasted at least 5 hr and was proportional to the dose of muscimol administered. The inhibitory effects of muscimol on newt sexual behaviors could be reversed by a single 100-microgram ip injection of arginine vasotocin. The inhibitory effects of confinement stress or corticosterone (CS) injections on newt sexual behaviors were blocked by pretreatment of newts with mercaptopropionic acid, a blocker of GABA synthesis. As well, bicuculline prevented the inhibition of sexual behavior induced by CS injection. These results support the conclusion that, in a male amphibian, the GABAergic system is involved in the inhibitory mechanisms regulating sexual behaviors and that CS mediates the stress-induced inhibition of sexual behaviors through the GABAergic system.     

Effect of cyclooxygenase-2 (COX-2) inhibitors in various animal models (bicuculline, picrotoxin, maximal electroshock-induced convulsions) of epilepsy with possible mechanism of action

Enzyme cyclooxygenase (COX) is reported to play a significant role in neurodegeneration and may play a significant role in the pathogenesis of epilepsy. Bicuculline (4 mg/kg; ip), picrotoxin (8 mg/kg; ip) and electroshock (60 mA for 0.2 sec) significantly induced convulsions in male Laka mice. COX-inhibitors viz. nimesulide (2.5 mg/kg; ip) and rofecoxib (2 mg/kg, ip) administered 45 minutes prior to an epileptic challenge prolonged mean onset time of convulsions, decreased duration of clonus and decreased % mortality rate against bicuculline- and picrotoxin-induced convulsions in mice. COX-2 inhibitors were ineffective towards maximal electroshock-induced convulsions. Nimesulide (1 mg/kg) and rofecoxib (1 mg/kg) also enhanced the effect of subprotective dose of muscimol against picrotoxin-induced convulsions. The result of the present study strongly suggests for a possible role of cyclooxygenase isoenzymes particularly, COX-2 in the pathophysiology of epilepsy and its GABAergic modulation.     

Nitric oxide mediates the interleukin-1beta- and nicotine-induced hypothalamic-pituitary-adrenocortical response during social stress.

We investigated the role of nitric oxide (NO) in the interleukin 1beta (IL-1beta) and nicotine induced hypothalamic-pituitary-adrenal axis (HPA) responses, and a possible significance of CRH and vasopressin in these responses under basal and social stress conditions. Male Wistar rats were crowded in cages for 7 days prior to treatment. All compounds were injected i.p., nitric oxide synthase (NOS) inhibitors, alpha-helical CRH antagonist and vasopressin receptor antagonist 15 min before IL-1beta or nicotine. Identical treatment received control non-stressed rats. Plasma ACTH and serum corticosterone levels were measured 1 h after IL-1beta or nicotine injection. L-NAME (2 mg/kg), a general nitric oxide synthase (NOS) inhibitor, considerably reduced the ACTH and corticosterone response to IL-1beta (0.5 microg/rat) the same extent in control and crowded rats. CRH antagonist almost abolished the nicotine-induced hormone responses and vasopressin antagonist reduced ACTH secretion. Constitutive endothelial eNOS and neuronal nNOS inhibitors substantially enhanced the nicotine-elicited ACTH and corticosterone response and inducible iNOS inhibitor, aminoguanidine, did not affect these responses in non-stressed rats. Social stress significantly attenuated the nicotine-induced ACTH and corticosterone response. In crowded rats L-NAME significantly deepened the stress-induced decrease in the nicotine-evoked ACTH and corticosterone response. In stressed rats neuronal NOS antagonist did not alter the nicotine-evoked hormone responses and inducible NOS inhibitor partly reversed the stress-induced decrease in ACTH response to nicotine. These results indicate that NO plays crucial role in the IL-1beta-induced HPA axis stimulation under basal and social stress conditions. CRH and vasopressin of the hypothalamic paraventricular nucleus may be involved in the nicotine induced alterations of HPA axis activity. NO generated by eNOS, but not nNOS, is involved in the stress-induced alterations of HPA axis activity by nicotine.     

CRF-dependent and CRF-independent mechanisms involved in hypophysial-adrenal system activation by bacterial endotoxin.

The immune system and the hypothalamic-pituitary-adrenal (HPA) axis play important role in the overall inflammatory response. The mechanism through which lipopolysaccharide (LPS, endotoxin) stimulates the HPA axis is not well understood. In order to clarify the role of hypophysiotropic peptides of paraventricular origin in the effect of LPS on ACTH and corticosterone secretion, the effect of LPS was studied on rats with lesions of hypothalamic paraventricular nucleus (PVN). It was shown that 90 min after 2 mg/kg LPS i.p. the ACTH, but not the corticosterone response was effectively blunted in PVN-lesioned rats, as compared to sham operated animals. However, in PVN-lesioned rats 240 min after treatment with LPS a significantly higher plasma ACTH and corticosterone level was monitored. It is, therefore, suggested that in response to LPS activation of HPA both CRF(s)-dependent and CRF(s)-independent mechanisms are involved, even a direct effect of the adrenal cortex should be taken into account.     

Intra-accumbens baclofen, but not muscimol, increases second order instrumental responding for food reward in rats

Stimulation of either GABA(A) or GABA(B) receptors within the nucleus accumbens shell strongly enhances food intake in rats. However the effects of subtype-selective stimulation of GABA receptors on instrumental responses for food reward are less well characterized. Here we contrast the effects of the GABA(A) receptor agonist muscimol and GABA(B) receptor agonist baclofen on instrumental responding for food using a second order reinforcement schedule. Bilateral intra-accumbens administration of baclofen (220-440 pmol) stimulated responding but a higher dose (660 pmol) induced stereotyped oral behaviour that interfered with responding. Baclofen (220-660 pmol) also stimulated intake of freely available chow. Muscimol (220-660 pmol) was without effect on responding for food on this schedule but did stimulate intake of freely available chow. Unilateral administration of either baclofen or muscimol (220 pmol) induced similar patterns of c-fos immunoreactivity in several hypothalamic sites but differed in its induction in the central nucleus of the amygdala. We conclude that stimulation of GABA(A) or GABA(B) receptors in the nucleus accumbens shell of rats produces clearly distinguishable effects on operant responding for food.